Antipsychotic-induced Adaptations in the Somatodendritic and Synaptic Physiology

抗精神病药物诱导的体细胞树突和突触生理学适应

• 批准号: 8150129
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 27.02万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150129
• 关键词: Affect; Antipsychotic Agents; Architecture; Axon; Brain; Cerebral cortex; Clozapine; Complement; Corpus striatum structure; Coupled; Disease; Electric Stimulation; Electrophysiology (science); GTP-Binding Proteins; Glutamates; Goals; Haloperidol; Laser Scanning Microscopy; Lasers; Mental disorders; Molecular; Morphology; Neurons; Physiological; Physiology; Population; Prefrontal Cortex; Probability; Property; Public Health; Schizophrenia; Slice; Symptoms; Synapses; Thalamic structure; Transgenic Mice; cell type; hippocampal pyramidal neuron; insight; mouse development; patch clamp; receptor; success; therapy development; two-photon

Antipsychotics that antagonize G-protein coupled, dopaminergic receptors alleviate the symptoms of schizophrenia. Prolonged treatment with antipsychotics 'remodels' circuits of the prefrontal cortex and striatum, ameliorating the symptoms of the disease. Our central hypothesis is that this remodeling depends upon the ability of antipsychotics to trigger cell-type specific adaptations in the synaptic connectivity, dendritic architecture and intrinsic excitability of striatal and cortical neurons. Dysregulation of these key sub-cellular regions is likely to be a central factor in schizophrenia and provides an obvious linkage to glutamatergic determinants in the disease. Yet, little is known about how antipsychotics and antipsychotic-sensitive receptors influence dendritic electrogenesis, synaptic integration and plasticity in functionally relevant subpopulations of striatal and PFC neurons. The central goal of the project is to help fill this gap in our understanding, but, there are obstacles to success. One is that the neurons within both the striatum and PFC are heterogeneous. Another major obstacle is the inaccessibility of dendritic regions to physiological study. This proposal takes advantage of BAC transgenic mice, the development of two photon laser scanning microscopy and two photon laser uncaging to overcome these obstacles. These approaches will be used in conjunction with electrophysiological, pharmacological and molecular strategies that complement the other Projects in this Conte Center to pursue three Specific Aims: 1) To characterize the impact of antipsychotic treatment on somatodendritic excitability and morphology of the two principal cell types in the striatum: striatonigral and striatopallidal medium spiny neurons (MSNs); 2) To characterize the impact of antipsychotic treatment on the properties of synapses formed by the two principal inputs to striatal MSNs from the cerebral cortex and thalamus; 3) To characterize the impact of antipsychotic treatment on the somatodendritic morphology and excitability of identified subsets of prelimbic/infralimbic (PL/IL) cortex pyramidal neurons.

抗精神病药可拮抗G蛋白偶联，多巴胺能受体减轻精神分裂症的症状。前额叶皮层和纹状体的抗精神病药“重塑”电路长期处理，改善了疾病的症状。我们的中心假设是，这种重塑取决于抗精神病药在突触连通性，树突结构以及纹状体和皮质神经元的突触连通性，树突结构以及内在兴奋性中触发细胞类型特异性适应的能力。这些关键的失调 亚细胞区域可能是精神分裂症的核心因素，并与谷氨酸能决定因素有明显的联系。然而，关于抗精神病药和抗精神病药敏感受体如何影响树突状的产生，突触的整合和可塑性在功能相关的纹状体和PFC神经元的功能亚群中，知之甚少。该项目的核心目标是帮助填补我们的理解，但是，成功的障碍。一个是纹状体和PFC中的神经元都是异质的。另一个主要障碍是树突状地区对生理研究的无法访问。该建议利用了BAC转基因小鼠，两种光子激光扫描显微镜的发展和两个光子激光渗透来克服这些障碍。这些方法将与电生理，药理学和分子策略一起使用，这些策略补充了该孔戴中心中其他项目以追求三个具体目标：1）表征抗精神病药物对抗精神病药物对两个主要细胞的体形兴奋性和形态学的影响 纹状体中的类型：纹状体和纹状体金属夹层神经元（MSNS）； 2）表征抗精神病药物对两个主要输入对纹状体皮质和丘脑纹状体MSN形成的突触特性的影响； 3）表征抗精神病药物对鉴定的前/异常/非中性比（PL/IL）皮质锥体神经元识别亚群的兴奋性的影响。